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Drug-Eluting Beads Chemoembolization (DEBDOX) for Hepatocellular Carcinoma in 2011: The Case for a Treatment Standard

Drug-Eluting Beads Chemoembolization (DEBDOX) for Hepatocellular Carcinoma in 2011: The Case for a Treatment Standard. JF Geschwind, MD Professor Radiology, Surgery, and Oncology Director, Vascular and Interventional Radiology Johns Hopkins University School of Medicine Baltimore, Maryland.

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Drug-Eluting Beads Chemoembolization (DEBDOX) for Hepatocellular Carcinoma in 2011: The Case for a Treatment Standard

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  1. Drug-Eluting Beads Chemoembolization (DEBDOX) for Hepatocellular Carcinoma in 2011:The Case for a Treatment Standard JF Geschwind, MD Professor Radiology, Surgery, and Oncology Director, Vascular and Interventional Radiology Johns Hopkins University School of Medicine Baltimore, Maryland

  2. 1. Why Drug-elutingTechnology? • Clear Rationale: • Maximize drug delivery • Consistent (scientifically reproducible) • Long lasting effect/slow release (sustained) • Tumor effect vs. systemic side effectsWE HAVE COME A LONG WAY!

  3. Symptomatictreatment BCLC staging system and treatment strategy HCC Stage 0PS 0, Child–Pugh A Stage A–CPS 0–2, Child–Pugh A–B Stage DPS >2, Child–Pugh C Very early stage (0) 1 HCC <2cmCarcinoma in situ Early stage (A) 1 HCC or 3 nodules<3cm, PST 0 Intermediate stage (B) Multinodular,PST 0 Advanced stage (C)Portal invasion, N1, M1, PST 1–2 End stage (D) 1 HCC 3 nodules ≤3cm Portal pressure/bilirubin Increased Associated diseases Normal No Yes Resection Liver transplantation PEI/RFA TACE Sorafenib Curative treatments Randomised controlled trials HCC = hepatocellular carcinoma; BCLC = Barcelona Clinic Liver CancerPEI = percutaneous ethanol injection; RFA = radiofrequency ablationTACE = transarterial chemoembolisation; PST = performance status Llovet JM, et al. J Natl Cancer Inst 2008;100:698–711

  4. Chemoembolization of Hepatocellular Carcinoma With Drug-Eluting Beads: Efficacy and Doxorubicin Pharmacokinetics 1000 DEB-TACE • 27 patients with Child-Pugh A • Response rate assessed by CT at 6 months • Response rate: 75% • 1- and 2-year survival: 92% and 89% (median follow-up of 28 months) 800 600 Doxorubicin at serum, ng/mL 400 200 0 baseline 5 min 20 min 40 min 60 min 2 h 6 h 24 h 48 h 7 d Time Post-Procedure 1000 Conventional TACE 800 600 Doxorubicin at serum, ng/mL 400 200 0 baseline 5 min 20 min 40 min 60 min 2 h 6 h 24 h 48 h 7 d Time Post-Procedure DEBDOX: DC Bead®, Drug-Eluting Bead doxorubicin Varela M et al. J Hepatology. 2006; 46(3):474-481.

  5. Single Center Phase II Trial of DEBDOX in Patients with Unresectable HCC Reyes D et al. Cancer J. 2009

  6. Kaplan-Meier Survival Curves 100 OS PFS 80 60 Survival Probability % 40 20 0 40 0 10 20 30 Time Months Reyes D et al. Cancer J. 2009

  7. PRECISION V: Overall 6-month Tumor Response Rates p = 0.11 Disease Control = Objective Response + Stable Disease Objective Response = Complete Response + Partial Response

  8. 6-month Response in More Advanced Patients DC Bead®demonstrated statistically significant advantage in advanced patients Objective Response (p=0.038) and Disease Control (p=0.026) P < 0.05

  9. PRECISION V trial1: DC Bead® was associated with a significantly lower incidence of doxorubicin-related AEs than cTACE DC Bead® cTACE 35 30 25 20 15 10 5 0 Alopecia Marrow suppression Mucositis Skin discoloration p=0.012* Incidence of doxorubicin-related AEs (%) DC Bead® is approved in 40 countries worldwide, including the USA (as LC Bead™) and Europe2 DC Bead® cTACE *p=0.0001 for analysis with assumption of independence of events 1. Lammer J, et al. Cardiovasc Intervent Radiol 2010;44:41–52 2. http://www.biocompatibles.com/media/press-releases/2009/06-08-2009.aspx AE = adverse event

  10. Prospective Randomized Comparison of Chemoembolization with Doxorubicin-Eluting Beads and Bland Embolization with Bead Block for Hepatocellular Carcinoma Malagari et al, Cardiovasc Intervent Radiol. 2009 Nov 24 • Evaluate the added role of a chemotherapeutic in TACE of intermediate-stage HCC • Group A (n = 41) DEBDOX • Group B (n = 43) bland embolization • EASL criteria and AFP • At 6 month: DEBDOX CR 27% PR 46% Bland embo CR 14% PR 42% • Tumor Recurrence: Bland embolization >> DEBDOX(78% vs. 46% at 12 months) • TTP: DEBDOX >>Bland embolization 42 +/- 9.5 vs. 36 +/- 9.0 weeks, p = 0.008

  11. Clinical Evidence *Survival data on DEBDOX are restricted to less than 4 years and longer term follow-up results will be published soon. **DEB vs TACE: p=0.11. DEB advantage for CP B/ECOG 1/bilobar or recurrence: p= 0.038. Fewer dox side effects: p=0.0001

  12. Conclusions DEBDOX: Proven Rationale Extension of cTACE Excellent PK profile Minimal toxicities Efficacy: Tumor response 75-85% EASL Survival: ~26 months BCLC B-C

  13. 2. How?Technical Considerations: Towards a Standardized Protocol • Drug delivery not embolotherapy! • 1. Choice of particle size • 2. Choice of drug: doxorubicin vs. irinotecan3. Catheter placement4. Actual delivery (how? Contrast or not?)5. End point (?)

  14. 1. Optimizing Drug Delivery: Importance of Particle Size

  15. IA Therapy for Vx-2 Liver Tumor:Iron-oxide Labeled Microspheres 300-500µm Distribution of iron oxide-containing Embosphere particles after transcatheter arterial embolization in an animal model of liver cancer: evaluation with MR imaging and implication for therapy. Lee KH, Liapi E, Vossen JA, Buijs M, Ventura VP, Georgiades C, Hong K, Kamel I, Torbenson MS, Geschwind JF. J Vasc Interv Radiol. 2008 Oct;19(10):1490-6.

  16. IA Therapy for Vx-2 Liver Tumor:Iron-oxide Labeled Microspheres 100-300µm

  17. Drug-Eluting Beads for liver embolization: Concentration of doxorubicin in tissue and in beads in a pig model 100-300μm or 700-900μm loaded with 37.5 mg dox/mL Livers analyzed 28 or 90 days after embolization DEBs eluted 43% of their initial drug load after 28 days and 89% after 90 days Drug detected at distances as far as 600μm from bead edge 100-300μm induced more necrosis than 700-900μm beads (p= .0036) MicroCT analysis: Small beads distal arteries + homogeneous distribution Doxorubicin concentration declines with increasing distances from the bead edge (still enough to be cytotoxic in vitro) Namur J et al. J Vasc Interv Radiol. 2010 Feb;21(2):259-67 Dreher M et al. GEST 2010

  18. 1. Optimizing Drug Delivery: Importance of Particle Size SMALL

  19. Complete necrosis on MR imaging DC Bead® [DEBDOX] in Patients with HCC

  20. Histological findings and tumor response 48 y/o female, right lobe lesion, s/p 3 treatments with DEBDOX Gross specimen after resection showing complete necrosis

  21. Histopathology: Extensive necrosis + no viable tumor cells DEB within necrotic tumor

  22. 2. Optimizing Drug Delivery: What drug? Doxorubicin: HCC, NET Irinotecan: CRC (?), No data

  23. 3. Catheter Placement Selective? YES 1.Better control 2.Minimize reflux 3.Better visualization of beads

  24. 65 yo woman Child B with large HCC: First Treatment

  25. Pre-treatment Post-treatment #1: Residual viable tumor

  26. Second Treatment

  27. MRI Post-treatment #2 No recurrence 29 months post initial treatment

  28. 4. Actual Delivery 1. Must use microcatheter 2. Use cone beam CT for targeting 3. Visibility of beads critical 4. Mix with contrast (4:1) 5. Inject slowly (1 ml/min)

  29. Usefulness of Cone Beam CT Imaging: Research and Clinical Use • Visualize the tumor • Target the tumor (drug delivery) • Proof of success = predicting response: • Tumor perfusion • Tumor segmentation

  30. DEBDOX in Patient with HCC: Usefulness of Cone Beam CT

  31. 5. End Points 1. Entire planned dose administered 2. Stop before stasis!! 3. No need for further bland embolization

  32. Conclusions Drug-Eluting Beads in 2011: Why, how and when? WHY? Rationale ESTABLISHED HOW? Technical considerations NEARING CONSENSUS (panel of experts) Bead size: Nearly there! SMALL >>large Drug: Doxorubicin (YES) vs. irinotecan (NO) Catheter position: SELECTIVE End point: FULL DOSE (no stasis) Unknown: Frequency treatment/dosing WHEN? HCC: Good data NET: On-going studies, CRC: On-going studies

  33. DISCLOSURES Grant support: Genentech, Bayer Healthcare, Nordion, Biocompatibles, Abdulmalik Research Fund, Alice Pratt Liver Cancer Fund, NIH/NCI, DOD, RSNA, SIR Consultant: Philips Medical System, Bayer Healthcare, Nordion, Biocompatibles, Guerbet, PreScience Patent: Use of 3-BrPA as an anti-cancer agent Founder: PreScience Pharma

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